Abstract
Bufadienolides are steroids that inhibit the Na+/K+ ATPase pump. Recent studies show that members of the bufadienolide family also inhibit the activity of aminopeptidase N (APN). APN is upregulated in different pathologies, including cancer and is a current target for drug development. Bufadienolides are cytotoxic in tumor cells, but there is no enough evidences that inhibition of APN activity contributes to their effect. In the present contribution we investigated the effect of another member of the bufadienolide family, bufotalin, on porcine APN (pAPN) activity. Bufotalin inhibited pAPN activity with K i values in the submicromolar range and an uncompetitive inhibition mechanism; it also inhibited porcine aminopeptidase A (pAPA) activity, but with a classical reversible competitive inhibition mechanism. In addition, we determined the effect of bufotalin on the viability/metabolism of APN+ A549, H292, MeWo and CT26 cancer cells. Bufotalin was cytotoxic in a dose dependent manner; the highest cytotoxicity was detected in A549 cells, the cells with the highest APN activity. Thus, tumor cell line sensitivity to the cytotoxic effect of bufotalin correlates with cell surface APN activity.
Funding source: Oficina de Gestión de Fondos y Proyectos Internacionales del Ministerio de Ciencia, Tecnología y Medio Ambiente de la República de Cuba
Award Identifier / Grant number: PN223LH010-010 2021-2023
Funding source: Ministerio de Ciencia, Tecnología y Medio Ambiente
Award Identifier / Grant number: Unassigned
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Research funding: This research was partially supported by a University Laboratory in Nanotechnology and Cancer (NaNoCancer) project: “New inhibitors of aminopeptidases with potential applications in cancer” (2016–2022), a grant from the “Oficina de Gestión de Fondos y Proyectos Internacionales del Ministerio de Ciencia, Tecnología y Medio Ambiente de la República de Cuba” (code PN223LH010-010 2021–2023), an IUBMB Mid-Career Program fellowship to I. Pascual Alonso for a research visit to IBt-UNAM, Mexico (2017), a UNU-Biolac fellowship to Laura Rivera (2020), and an Organization for the Prohibition of Chemical Weapons (OPCW) fellowship to I. Pascual Alonso (2022).
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